Cancer is the most devastating disease to modern society because there are no effective treatments that do not incur side effects. Although many treatments are available for cancer treatment, including surgery, radiation, phototherapy, and chemotherapy, used alone or in combination, it is still a challenging task to cure cancer.
Achieving clinical efficacy with the current chemotherapeutic drugs remains a significant challenge despite their strong efficacy in preclinical experiments; this difficulty is mostly due to their lack of tumor selectivity. The major issue is that only a fraction of anticancer drugs are actually delivered to the tumor tissues after the administration of chemotherapeutic drugs. The ineffective drug delivery of current chemotherapeutics results in a low intra-tumoral drug concentration, which decreases their chemotherapeutic efficacy. Furthermore, the administered anticancer drugs are mostly delivered to healthy tissues and thus cause various adverse side effects, such as bone marrow dysfunction, gastrointestinal disorders, alopecia, and immune dysfunction. Therefore, ineffective targeting of anticancer drugs eventually contributes to the development of multidrug resistance in tumor tissues and nonspecific toxicity in healthy tissues.
Therefore, to overcome the low efficacy and severe side effects of current therapeutics, it is essential to deliver more drug to tumor tissues and less drug to healthy tissues. Therefore, many researchers have studied ways to achieve selective targeted drug delivery to the tumor site.
One way to achieve selective drug targeting to solid tumors is to exploit the phenomenon of Extended Permeability and Retention, EPR, which is based on the abnormalities of the tumor vasculature (Maeda et al., J Controlled Release, 2000, 65: 271-284). Rapidly growing solid tumors feature widespread angiogenesis to meet the high metabolic needs of the tumor. The resulting blood vessels in angiogenesis-dependent solid tumors contain endothelial pores in the vascular membrane, which range in size from 10 nm to 1,000 nm. This leaky vasculature in tumor tissues enhances the vascular permeability of particles circulating in the blood. In addition, the impaired lymphatic system in tumor tissues enhances the retention of penetrated particles, particularly nano-sized macromolecules or nanoparticles. Thus, nanoparticles loaded with anticancer drugs can selectively extravasate from the systemic circulation to tumor tissues, resulting in preferential accumulation at much higher concentrations in tumor tissues than in healthy tissues or organs. Nanoparticle drugs have been demonstrated to selectively accumulate in tumors through the EPR effect, and this type of drug delivery is called passive targeting (Fang et al., Adv. Drug Delivery Rev., 2011, 63: 136-151; Danhier et al., J Controlled Release, 2010, 148: 135-146).
Abraxane® (Celgene Co.) is the first commercialized anticancer nanoparticle for metastatic breast cancer (U.S. Pat. Nos. 6,506,405, 6,537,579). Abraxane® is simply albumin-bound paclitaxel, i.e., the mitosis-inhibiting anticancer drug paclitaxel with albumin as the base material. This carrier does not contain an additional active targeting moiety, with the selective accumulation mostly depending on passive targeting. However, the tumor targeting efficiency of Abraxane® is enhanced less than 1.5-3 times compared with paclitaxel, due to its unstable nanostructure, which is not sufficient to significantly reduce side effects (Desai et al., Clin Cancer Res, 2006, 12: 1317-1324).
Ideally, nanoparticles should deliver cytotoxic drugs specifically to the targeted tumor tissues. To achieve efficient tumor targeting, nanoparticles need to exploit not only passive targeting by maintenance of a stable nanostructure but also active tumor-targeting by presenting tumor-targeting moieties on the nanoparticle surface. Many research teams have developed various nanoparticles with tumor targeting moieties (A. Swami et al., Multifunctional Nanoparticles for Drug Delivery Applications: Imaging, Targeting, and Delivery, Chapter 2. Nanoparticles for Targeted and Temporally Controlled Drug Delivery, p 9-p 29, Springer, 2012). However, these efforts have failed to achieve the commercialization of “targeting moiety nanoparticles,” as described below.
Nanoparticles comprising only 2 components, a drug and a base material, can be relatively easily manufactured without covalent bonding by selecting a base material that is compatible with the intended anticancer drug. However, it is very difficult to prepare stable “targeting moiety nanoparticles” comprising 3 components, i.e., a drug, a base material, and a targeting moiety, without covalent bonding. To obtain a stable nanostructure, 3-component nanoparticles could be prepared by covalently bonding either the drug or the targeting moiety to the base material and then combining the third component with this complex. Unfortunately, the use of covalent bonds to prepare stable nanoparticles can cause the following problems. 1) Covalent bonding results in the formation of a new material that differs from the material prior to bonding. For instance, covalent bonding between hydrogen and oxygen forms the new molecule, water. Therefore, it is unavoidable for covalent bonding to form a new chemical entity, NCE. NCEs with new physicochemical properties could have unpredicted toxicities. 2) Covalent bonding of a drug changes its chemical structure, potentially negatively affecting its anticancer efficacy. 3) Covalent bonding of a targeting moiety changes its chemical structure, potentially negatively affecting its tumor targeting ability.
Another reason for the failure of “targeting moiety nanoparticles” is that attaching the targeting moiety to enhance tumor targeting can affect the structural stability of the nanoparticles and thus the capacity for passive targeting, preventing the tumor targeted delivery of the nanoparticles.
Another reason for the failure of “targeting moiety nanoparticles” is the technical difficulty involved in preparing a single nanoparticle made up of multiple heterogeneous components such as anticancer drugs, the base material, and targeting moieties, even with the incorporation of covalent bonding. Due to the technical challenges in the formation of a stable nanostructure with multiple components, many nanoparticles have been developed containing non-biological components such as metal (U.S. Pat. Nos. 7,364,919, 7,829,350, 8,236,284, 8,246,995, US Patent Pub. No. 20120052006, EP1671625, WO2002/098364, WO/2012/106713, WO/2012/075087). Unfortunately, nanoparticles containing non-biological components with anticancer efficacy in animal experiments failed to show good clinical efficacy but did exhibit serious toxicity.
The impact of binding targeting moieties to nanoparticles can be clearly observed in the case of “targeting moiety nanoparticles” in which porphyrin was covalently bound (conjugate) to serum albumin (Chang et al., Pharm. Res. 2012, 29:795-805). Serum albumin is the best base material for nanoparticles because of its harmlessness and its ability to non-covalently bind many different organic chemicals. Porphyrin, a precursor of heme, is a major targeting moiety that is able to accomplish tumor targeting for most cancer cells.
This nanoparticle with porphyrin covalently bound to albumin (conjugation) was expected to increase drug delivery efficiency. However, the anticancer efficacy was not significantly improved for the reasons mentioned above. In fact, the drug delivery efficiency of nanoparticles in which the targeting moiety porphyrin was conjugated to serum albumin was worse than that of nanoparticles in which only serum albumin was used for encapsulation (Chang et al., Pharm. Res. 2012, 29:795-805; Desai et al. Clin Cancer Res. 2006; 12:1317-1324).
As mentioned above, nanoparticles with active targeting moieties covalently bound at the surface are often thought to be superior to simple passively targeted nanoparticles, but none has reached commercialization due to the technical problems in preparing “targeting moiety nanoparticles”.
The current commercially available nanoparticles are passively targeted nanoparticles in which the base material and anticancer drugs are non-covalently associated, including Abraxane, Doxil, Myocet, and Daunoxome. Therefore, there is an urgent need to develop structurally stable “targeting moiety nanoparticles” that consists of a non-toxic base material and a targeting moiety non-covalently bound at the surface.
Here, the present inventors tried to solve these problems and discovered a novel targeting-enhanced nanoparticle consisting of non-toxic serum albumin as the base material and porphyrin compound as the tumor targeting moiety. These nanoparticles were used to non-covalently encapsulate anticancer drugs, thereby avoiding structural changes in both the anticancer drugs and the tumor targeting moiety. The present inventors confirmed that 1) the drug maintains its anticancer efficacy without alteration; 2) active tumor targeting was enhanced by the preservation of the tumor targeting ability of the targeting moiety at the surface; 3) passive tumor targeting was enhanced by structural stability.